Chemistry Commons^™

Development Of Salinomycin Derivatives As Potential Anticancer Agents, Viren Soni

Theses and Dissertations

Salinomycin is a poly-ionophore antibiotic that was originally isolated from Streptomyces albus by Miyazaki and colleagues from Kaken Chemicals Co., Ltd., Tokyo, Japan. Salinomycin exhibits antimicrobial activity against Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, Micrococcus flavus, Sarcina lutea, Mycobacterium spp. Some filamentous fungi, Plasmodium falciparum, and Eimeria spp. as well as protozoan parasites responsible for the poultry disease coccidiosis. Hence, it is used in veterinary medicine. In 2009 Gupta et al demonstrated that salinomycin selectively killed human breast cancer stem cells (CSCs) with great efficacy, and the mechanism of action of this novel CSCs molecule was explored. To name …

Analyzing Novel Metal Alloys For Glucose Sensing And Electrocatalysis, Anna Grace Boddy

Theses and Dissertations

In pharmaceutical and medicinal chemistry, metals and metal alloys often receive less attention compared to biological or organic compounds due to many factors including toxicity in the body for drug development or the cost of these metals. However, metals can play an important role in pharmaceuticals, having an impact on original cancer drugs, such as platinum used for head and neck tumors. Electrocatalysis is also another topic that receives less attention over topics such as chromatography in pharmaceuticals due to its potential toxic catalysts and voltages that could be harmful to the body. Electrocatalytic sensors can play an important role …

Covalent Inhibition Of Enzyme Sortase A As A New Pathway Against Bacterial Resistance Of Staphylococcus Aureus, Umyeena Bashir

Master's Theses

The continued rise of antibiotic-resistant bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus), has made the discovery of novel antibiotics critical. While bacteriostatic and bactericidal antibiotics inevitably exert evolutionary pressure on bacteria to develop resistance, small molecules that target mechanisms of bacterial virulence present a promising alternative for treatment. Sortase A (Srt A), a cysteine protease of S. aureus, promotes bacterial virulence by covalently attaching proteins such as pilin to the bacterial surface, enabling bacterial adhesion to mammalian cells. Inhibitory studies of this enzyme have gained prominent interest as a new pathway for drug development since blocking this enzyme's ability to …

Polymer-Based Nanotherapeutics To Combat Difficult-To-Treat Bacterial Infections, Jessa Marie V. Makabenta

Doctoral Dissertations

The continuous emergence and spread of antibiotic-resistant bacteria are a global health emergency, debilitating the capability to prevent and cure various infectious diseases that were once treatable. Antibiotic therapy is further rendered ineffective due to biofilm formation and the ability of bacteria to thrive and colonize inside mammalian cells. Given the diminishing efficacy of available antibiotics combined with the scarcity of new therapeutics entering the antibiotic pipeline, innovative treatment strategies are urgently in demand. Nanomaterial-based strategies offer ‘outside of the box’ approach for the treatment of antibiotic-resistant bacterial infections. Nanomaterials feature tunable physicochemical properties that can be carefully modified to …

Synthesis And Evaluation Of Novel Nucleotide Prodrugs Against Sars-Cov-2, Mohammed Attaelmanan

Electronic Thesis and Dissertation Repository

Positive sense RNA (ribonucleic acid) viruses (+ssRNA) are the known causative agents of diseases throughout history. These includes Hepatitis C Virus (HCV), SARS-CoV, and recently SARS-CoV-2. RNA dependent RNA polymerase (RdRp), a critical enzyme in the life cycle of the virus, can be targeted by using nucleotide antivirals thus causing inhibition. Novel ribonucleotides antiviral agents that possess nucleobase modifications and a 5′-phosphoramidate prodrug moiety, referred to as a ProTide, have been synthesized. The ribonucleoside analogues were constructed by CuI catalyzed azide-alkyne cycloaddition chemistry (CuAAC), also referred to as ‘click’ chemistry. The synthetic route utilized 5-ethynylpyrimidines and azidoribofuranoses as CuI ‘click’ …

Investigating The Activity Of Alternative Warheads For Targeted Covalent Inhibition Of The Inhibitor Vertebrate Lysozyme Protein From Pseudomonas Aeruginosa, Katie Hambrick

Master of Science in Chemical Sciences Theses

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative bacterium that causes blood and lung infections in hospital environments due to its ability to survive on improperly sterilized medical equipment. P. aeruginosa has developed several multi-drug resistance mechanisms that make it very difficult to treat with current antibiotics.¹ This presents the need for a new class of antibiotics that cannot be overcome by P. aeruginosa’s mechanisms of resistance.

The primary goal of this project was to develop a small library of inhibitors that could later be incorporated into lead compounds for novel antibiotic drug discovery. One of P. …

The Development Of Novel Radioimmunoconjugates For The Pet Imaging And Radioimmunotherapy Of Cancer, Samantha M. Sarrett

Dissertations, Theses, and Capstone Projects

Antibodies have long played a vital role in nuclear medicine for both the diagnosis and therapy of various malignancies. The role and development of antibodies in nuclear medicine can be broadly separated into three different categories: 1) bioconjugation strategies, 2) immunoPET imaging, and 3) radioimmunotherapy. This dissertation will attempt to comprehensively cover each of these categories through a series of studies, protocols, and reviews. For the bioconjugation strategies, we will describe the development of a novel site-selective bioconjugation strategy using an innovative lysine-targeting reagent, PFP-bisN₃, to prepare [⁸⁹Zr]Zr-^SSKDFO-pertuzumab for visualizing HER2+ breast cancer. Further, …

Development Of New Chemical Probes To Delineate The Polyamine Regulation & Molecular Strategies To Unravel Protein Polyamination, Vennela Tulluri

Theses and Dissertations

Polyamines such as putrescine, spermidine, and spermine modulate critical cellular processes, including gene expression and cell proliferation. Cellular polyamine regulation is a complex mechanism controlled by three different proteins: Ornithine decarboxylase (ODC), Antizyme (OAZ), and Antizyme Inhibitor (AZIN). While ODC is directly involved in polyamine biosynthesis, OAZ, and AZIN regulate the ODC activity via protein-protein interactions. The dysregulation of ODC, OAZ, and AZIN leads to elevated polyamines in numerous pathologies, making them attractive targets for controlling polyamine levels. Besides regulating polyamine synthesis, OAZ modulates polyamine transport. However, the precise mechanism remains elusive. In this research, we discuss our approach to …

Anxiety-Like Behavior In C57bl/6j Mice Is Sexually Dimorphic And Altered By Buprenorphine, Ohm Sharma

Chancellor’s Honors Program Projects

No abstract provided.

Synthesis And Analysis Of Novel Troponoid-Based Chemical Probes, Alex Berkowitz

Dissertations, Theses, and Capstone Projects

Troponoids are a class of non-benzenoid aromatic species featuring a cycloheptatrienone ring and varying degrees of oxygenation. These scaffolds have proven ubiquitous amongst natural products, and have displayed promise as therapeutic agents against a variety of diseases. Herein, we will describe our efforts towards furthering troponoids as potential pharmaceuticals. In Chapter 1, we outline a kojic acid-derived oxidopyrylium cycloaddition/ring-opening method developed in our lab to generate ahydroxytropolones (aHTs). This route was successfully adapted to synthesize a small library of lipophilic aHTs that were proven to be effective against herpes simplex virus-1 (HSV-1) replication, while providing further insight into the mechanism …

Investigating The Interactions Of The Iron-Sulfur Mitochondrial Protein, Mitoneet With Its Binding Partners, Ebenezer Osei Newton

Graduate Theses, Dissertations, and Problem Reports

MitoNEET belongs to the CDGSH Iron-Sulfur Domain (CISD)-gene family of proteins and is a [2Fe-2S] cluster-containing protein found on the outer membrane of mitochondria. The specific functions of mitoNEET/CISD1 remain to be fully elucidated, but the protein is involved in regulating mitochondrial bioenergetics in several metabolic diseases. Unfortunately, drug discovery efforts targeting mitoNEET to improve metabolic disorders are hampered by the lack of ligand-binding assays for this mitochondrial protein. We have developed a protocol amenable for high-throughput screening (HTS) assay, by modifying an ATP fluorescence polarization method to facilitate drug discovery targeting mitoNEET. Based on our observation that adenosine triphosphate …

Synthesis And Pharmacology Of Illudalic Acid And Analogous Chemical Structures, Robert Gaston Jr

Graduate Theses, Dissertations, and Problem Reports

Natural products are the foundation of modern medicine and an inspiration for chemical innovation. Developing new synthetic strategies to complex natural products drives synthetic innovation and promotes pharmacological exploration. As bioactive secondary metabolites of fungi, illudalic acid and associated analogs have unrealized medicinal potential due to synthetic limitations. Illudalic acid is notably the first selective covalent inhibitor of the LAR-PTPs, a class of enzymes linked to many human illnesses, including stimulant addiction. The chemistry herein focuses on optimizing synthetic routes to illudalic acid and associated analogs toward exploring their pharmaceutical potential. We report a second-generation synthesis of illudinine (55% overall …

Enantioselective Dearomatization Facilitated By Non-Covalent Interactions Of N-Heterocyclic Carbene Catalysts And Pyridinium Salts, Jack A. Patterson

Graduate Theses, Dissertations, and Problem Reports

Dihydropyridines are a practical organic scaffold commonly used for their pharmaceutical properties. Nucleophilic dearomatization of pyridines has proven to be a useful method in obtaining dihydropyridines. By using N-heterocyclic carbene (NHC) organocatalysts, dihydropyridines can be synthesized with high regioselectivity of the 1,4 regioisomer over the 1,2- regioisomer but often with low enantioselectivity. By incorporating non-covalent interaction contact points, we hypothesize that enantioselectivity can be enhanced. By synthesizing numerous NHCs, each proposed to exhibit a different type of non-covalent interaction (i.e., hydrogen bonding or ion pairing), an understanding of the secondary interactions within this reaction system can be studied and …

Application Of Mass Spectrometry For The Characterization Of Synthetic Oligomers And Natural Lignin, Poorya Kamali

Theses and Dissertations--Chemistry

As part of the ongoing effort to substitute finite fuel and chemical resources with renewable ones, biomass is emerging as one of the most promising sources. Biomass consists of three main components of cellulose, hemicellulose, and lignin. Traditionally, cellulose has been used extensively in pulping industry, while lignin has been considered waste and is burned to generate heat. Lignin, a complex aromatic polymer component of biomass, has the potential to be used as a source of aromatic chemicals and pharmaceutical synthons. The recalcitrant nature of lignin, the lack of effective lignin breakdown methods and analytical techniques to analyze it are …

Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1, Austin Hachey

Theses and Dissertations--Chemistry

The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this …

The Discovery And Characterization Of Novel Potent 5-Substituted 3, 3’, 4’, 7-Tetramethoxyflavonoid Dna Triplex Specific Binding Ligands, Vanessa Marie Rangel

University of the Pacific Theses and Dissertations

Chemotherapy works by killing fast dividing cells. Unfortunately, these drugs are not specific to cancer tissue and can damage normal cells. Chemotherapy is like taking poison and hoping it kills the cancer cells before it kills you. As an alternative, many researchers have investigated the use of antigene therapy to selectively target cancer causing genes to avoid off target effects. Although promising, the theory is limited by the stability of the triplex structure. Here, we report the discovery of potent triplex binding ligands derived from the natural product quercetin. Chemical derivatives of 5-substituted 3, 3’, 4’, 7-tetramethoxyquercetin derivatives were characterized …

Gold (I) Tetrathiomolybdate Clusters: Synthesis, Characterization, Computational Studies, And Reactivity With Thiophenol And Selenophenol, Dhirgam Humaidy

Electronic Theses and Dissertations

This thesis describes the synthesis and reactivity of heterometallic complexes containing medicinally active Au(I) and tetrathiomolybdate, [MoS₄]^2-. The research is motivated by the idea of multifunctional drugs, which are designed to treat diseases through two or more mechanisms of action. Five clusters of the general form, [MoS₄(AuL)₂] were prepared: C-1 (L=IPr), C-2 (L=IBzMe), C-3 (L=IMes), C-4 (L=PPh₃), and C-5 (L=PEt₃). The clusters with NHC ligands, C-1, C-2, and C-3 were prepared for the first time and thoroughly characterized by ¹H NMR,¹³C{¹H} …

Investigating The Effects Of Ionic Liquids On Dna Gquadruplex And Protein Structure Using Molecular Dynamics Simulations, Nicholas J. Paradis

Theses and Dissertations

Nucleic acids and proteins have huge implications in biomedicine and bioengineering, however their storage instability limits their applicability and current storage protocols are expensive and globally-inaccessible. Finding an alternative biocompatible media to store nucleic acids and proteins would reduce costs and increase their applicability. Ionic liquids (ILs) are molten salt compounds that have been shown to modulate the stability and activity of nucleic acids and proteins. In this thesis, molecular modeling studies of DNA/RNA and protein structure in ILs will be discussed (Chapter 1) and this method will be used to study the IL effects on the structure on the …

Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian

Doctoral Dissertations

The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …

Intracellular Delivery Of Therapeutic Biomolecules Through Versatile Polymer Nanotechnology, David C. Luther

Doctoral Dissertations

Advancing pharmaceutical technology has made it possible to treat diseases once considered ‘undruggable.’ Access to these new pharmaceutical targets is possible thanks to the advent of protein and nucleic acid therapeutics. Responses to the COVID-19 pandemic, as well as cutting-edge treatments for cancer and multiple sclerosis have centered on these biologic therapies, promising even greater value in the future. However, their utility is limited at a cellular level by inability to cross the plasma membrane. Nanocarrier technologies encapsulate therapeutics and facilitate uptake into the cell but are often trapped and degraded in endosomes. Arginine-functionalized gold nanoparticles (Arg-NPs) provide efficient, direct …

Investigation Of The Stability Of Arsenoplatins In Saline Solution Using Reverse-Phase High-Performance Liquid Chromatography, Amber Rojas

University Honors Program Senior Projects

The pursuit of novel platinum(II)-based drugs has been driven by adverse side effects and resistance to current FDA-approved antineoplastic platinum drugs, such as cisplatin. The discovery of a synergistic effect between the FDA-approved anticancer drugs arsenic trioxide and cisplatin in vitro inspired the synthesis of complexes containing the moieties of both drugs. Arsenoplatins (APs) are novel and promising chemotherapeutic agents with an arsenous acid moiety attached to a platinum(II) center. Based on the NCI-60 (NCI = National Cancer Institute) screen, the first member of the family, arsenoplatin-1 (AP-1), has shown greater cytotoxicity than cisplatin or arsenic trioxide in various cancer …

Identification And Quantitation Of Unspecified Impurities Discovered In Novel Oral Irinotecan By Lc-Ms/Ms And Uhplc, Laura B. Miller

Forensic Science Master's Projects

Irinotecan is a cancer medication approved for medical use in the United States in 1996. It is currently administered via intravenous injection. However, intravenous dosing has disadvantages such as requirement of administration by a trained professional in a medical facility, possible severe adverse effects, pain at the injection site, and possible hemolysis if injected too rapidly. Previously oral administration was not feasible because the p-glycoprotein (p-GP) on the cell membrane of stomach cells acts as a defense mechanism against harmful substances by pumping the irinotecan back into the intestinal lumen for excretion. With the discovery of the p-GP inhibitor encequidar …

Synthetic Investigations In Chemical Probe Development Part 1: Design And Synthesis Of Novel Triton X-405 Adenosine Conjugates; Part 2: Synthesis Of 2,8-Dihydroxychrysene, Rachel Irene Hammond

Honors Theses

Although not drugs themselves, chemical probes are a necessary tool in biomedical research for the interrogation of biological systems. In the present synthetic investigation, two chemical probes were developed – a Triton X-405 adenosine conjugate (TX-405A) and 2,8-dihydroxychrysene. The designed TX-405A conjugate was generated in four steps through tosylation and amination of TX-405 such that EDC-coupling of TX-amine with 2’,3’-Isopropylidene adenosine-5’-carboxylic acid afforded TX-405A following acetonide deprotection. The development of TX-405A represents the first report of the synthesis and utilization of a detergent-linked dosimeter. The synthesis of 2,8-dihydroxychrysene provided an in-depth exploration on the unique reactivity of chrysene. The desired …

The Design Of A Pcr-Based Assay To Detect And Isolate The Serine Palmitolytransferase Gene From Environmental Bacteria, Lana Taylor

Honors Theses

Sphingolipids are a natural class of lipids that function as structural elements of cell membranes and signaling molecules for important cellular activities such as cell growth, differentiation, apoptosis, recognition, and adhesion. These lipids can be found universally in eukaryotic cells as well as some species of bacteria, such as those found in the human gut microbiome and in the environment in soils. Though sphingolipid production is rare in bacteria, both eukaryotic and prokaryotic sphingolipid biosynthesis begin with the condensation of serine and palmitoyl CoA into 3-ketodihydrosphingosine catalyzed by the enzyme serine palmitoyltransferase (SPT). In recent years, several studies have shown …

Hepatocellular Carcinoma Image-Guided Intervention: Quantitative Characterization Of Reagents For Thermochemical Ablation, Emily A. Thompson

Dissertations & Theses (Open Access)

Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma, a leading cause of cancer death worldwide. TCA utilizes acid-base chemistry delivered simultaneously to induce local ablation when administered. When delivered via a mixing catheter placed directly into the tumor, acid (e.g., AcOH) and base (e.g., NaOH) react to completion at the catheter tip, producing the acetate salt, water, and releasing heat (Δ>50°C) in sufficient quantities to induce lethal osmotic and thermal stress in tumor cells. However, these two reagents are not distinguishable from tissues with noninvasive imaging modalities, which makes monitoring the delivery of TCA …

Drug Loaded Mesoporous Nanocarriers For The Detection Of Aspergillosis, Madeline Jewel Brooks

Honors Capstone Projects and Theses

No abstract provided.

The Use Of Hallucinogens In The Treatment Of Mental Health Disorders, Brianna Gagen

Honors College Theses

The percent of people with mental health disorders in the United States have skyrocketed over the past decade. With stigma surrounding the discussion of mental health and the symptoms associated with it, often those that are suffering do not receive sufficient treatment, as they might with a physical illness. The current, common treatment options for common psychological disorders, like depression, anxiety, and post-traumatic stress disorder, are sometimes not effective in patients, due to resistance or poor response outcomes. Consequently, in order to research alternative therapeutic approaches for mental health disorders, scientists are researching the effects of several hallucinogenic drugs in …

Extraction And Partial Purification Of An Antibiotic-Like Compound From The Soil Bacterium Rhodococcus Strain Kchxc3, Elizabeth Bond

Undergraduate Honors Theses

Rhodococcus bacteria have many secondary metabolic pathways that may produce novel natural products. The bacterium Rhodococcus strain KCHXC3 was isolated from a soil sample collected near Kingsport, Tennessee and was found to produce an inhibitory compound active against a broad array of bacterial species, including the Gram negative pathogen Shigella sonnei. The aim of this research is to extract and purify the compound for future structure elucidation. A mixture of compounds from 3 month old agar plates inoculated with strain KCHXC3 was extracted using ethyl acetate. The crude extract was then partially purified utilizing a Sephadex LH-20 column, followed …

An Investigation Towards The Synthesis Of A Novel Conformationally Restricted Ethylenediamine Scaffold, Fanny Mai

Theses, Dissertations and Culminating Projects

This study reports the synthesis of a novel conformationally restricted ethylenediamine scaffold that can be explored for drug discovery. There was significant progress in synthesizing the target scaffolds, but future studies are needed to finish this synthesis. This potential ethylenediamine compound may offer new scaffolds for exploration in drug design and orexin receptor antagonists with improved selectivity for OX1R and OX2R.

The Design Of A Efficient Production And Purification Of Fibroblast Growth Factor 2, Mandeep Kaur

Chemistry & Biochemistry Undergraduate Honors Theses

Chronic wounds pose a major problem in the United States with an estimate of twenty-five million dollars a year spent on associated treatments. Growth factors can be used as a potential treatment for chronic wounds since they promote cell proliferation and angiogenesis. This study employs one specific growth factor, fibroblast growth factor 2 (FGF2) so that it could potentially be used in future treatment. Wild-type FGF2 is thermally unstable, and it has a mean elimination time of 7.6 hours. This study attempted to improve upon its stability through a mutation on the heparin binding loop. The mutation performed was K134E. …